CYTOKINE EXPRESSION IN HUMAN &EXPERIMENTAL HEART FAILUR

University Of Colorado Denver, Aurora CO

Investigators

Linked publications & trials

Abstract

Although the last ten years have seen dramatic improvements in the therapeutic approach to CHF, the expanding number of those afflicted with this disease and its persistent poor prognosis make it clear that additional novel approaches are necessary. In this regard, there has recently been an increasing appreciation of an important inflammatory component in both the development and progression of the failing heart. Specifically, increased levels of several pro-inflammatory cytokines have been found to be elevated in patients with advanced stage disease and appears to correlate with a worse prognosis. The investigations proposed in this proposal are unique and timely in two major areas: First, with the efforts of our collaborators at The University of Colorado and Temple University, these investigations will address the hypothesis that local intra-cardiac production of interleukin-1 plays a substantive role in the progression to decompensated congestive heart failure in the human heart. This will be assessed under circumstances of both established heart failure and the regression following left ventricular unloading by way of LVAD support. Second, using the well established experimental model of post-infarction cardiac failure they ask whether altering the expression/effect of such cytokines will change the transcriptional program of myocardial cells in a way associated with improved function and/or a more favorable and adaptive, remodeling process after injury. The overall hypothesis of this project is that the intra-cardiac expression of the pro-inflammatory cytokine IL-1beta is both a marker of, and progression factor for, the transition to decompensated congestive heart failure. Based on this idea, our secondary hypothesis is that interventions blocking the expression and/or effects of this cytokine will be associated with improved myocardial function and subsequently prognosis. The methods to be employed include the analysis of cytokine expression and down-stream transcriptional regulators from human samples either at the time of primary cardiac transplantation or at the time of LVAD placement and secondary transplantation. Similarly, analysis of these genes will be done in an established model of experimental heart failure in an attempt to: (1) correlate gene expression with hemodynamic severity of cardiac failure and (2) determine if targeting the expression and/or effect of IL-1 in the post-infarct heart is associated with more functional alterations in gene expression and function.